ALLOIMMUNITY IN AUTO IMMUNE DISEASE

自身免疫性疾病中的同种免疫

• 批准号: 6170383
• 负责人: J. Lee Nelson
• 金额: $ 29.99万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6170383
• 关键词: DNA; autoantibody; autoimmune disorder; cell migration; cell population study; clinical research; disease /disorder etiology; flow cytometry; histocompatibility; histocompatibility typing; human genetic material tag; human subject; in situ hybridization; membrane permeability; pathologic process; placental transfer; pregnancy immunology; systemic lupus erythematosus; tissue /cell culture

Advances with molecular biological techniques have led to the appreciation that there is bi-directional traffic of cells during pregnancy. Fetal cells are found in maternal peripheral blood in the majority of first pregnancies and evidence for maternal cells has been found in over 40 percent of cord blood samples. Recently, the surprising observation was reported that fetal cells also can persist in maternal blood for decades after pregnancy completion. This observation raises the important question as to whether maternal cells also persist long-term in some offspring. It is well known that maternal cells engraft and persist in infants with severe combined immunodeficiency, but no previous study has investigated long-term persistence of maternal cells in normal individuals. In support of this probability, a cytogenetic study of male infants who received in utero transfusions from their mothers revealed some lymphocytes were XX at more than five years of age. In initial studies from our laboratory we report evidence for long-term persistence of maternal cells in some individuals up to 47 years after birth. Bi-directional traffic of cells during pregnancy, and long-term persistence of microchimerism in some individuals, when considered together with observations in experimental models and in human diseases characterized by chimerism (nonhost cells), led the investigator to propose the hypothesis that alloimmunity may contribute to some autoimmune disease. Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease for which a well-recognized experimental model involves the introduction of parental cells into F1 progeny. Some manifestations of SLE are also mimicked in human chronic graft-versus-host-disease that occurs after allogenic hematopoietic stem cell transplantation. The studies in this proposal are designed to investigate the hypothesis that maternal cells and/or DNA persist in some progeny and that maternal microchimerism contributes to the pathogenesis of some autoimmune diseases, specifically SLE. The proposed studies will investigate qualitative and quantitative aspects of persistent maternal microchimerism. To further address pathogenicity disease-affected tissues of SLE patients will be examined for maternal DNA and cells. The HLA- relationship of mother and her progeny will be investigated as a potential factor in the persistence and/or pathogenicity of persistent maternal microchimerism. The studies that are proposed may result in a new understanding of immunologic aspects and consequences of pregnancy. If persistent maternal microchimerism is involved in the pathogenesis of SLE new therapeutic modalities could be developed on this basis.

分子生物学技术的进步使人们认识到妊娠期间细胞存在双向运输。 大多数首次妊娠的母体外周血中都发现了胎儿细胞，并且在超过 40% 的脐带血样本中发现了母体细胞的证据。最近，有报道称，令人惊讶的观察结果是，胎儿细胞在妊娠完成后也可以在母体血液中持续存在数十年。 这一观察结果提出了一个重要问题：母体细胞是否也能在某些后代中长期存在。 众所周知，母体细胞在患有严重联合免疫缺陷的婴儿中植入并持续存在，但之前没有研究调查母体细胞在正常个体中的长期持续存在。 为了支持这种可能性，一项针对在子宫内接受母亲输血的男婴的细胞遗传学研究显示，一些淋巴细胞在五岁以上时为 XX。 在我们实验室的初步研究中，我们报告了某些个体母体细胞在出生后长期持续存在的证据，长达 47 年。怀孕期间细胞的双向运输以及某些个体中微嵌合体的长期持续存在，与实验模型和以嵌合体（非宿主细胞）为特征的人类疾病中的观察结果结合起来考虑，使研究人员提出了同种免疫可能导致某些自身免疫性疾病的假设。 系统性红斑狼疮 (SLE) 是一种典型的自身免疫性疾病，其公认的实验模型涉及将亲本细胞引入 F1 后代中。 SLE 的一些表现也与同种异体造血干细胞移植后发生的人类慢性移植物抗宿主病相似。本提案中的研究旨在调查以下假设：母体细胞和/或 DNA 在某些后代中持续存在，并且母体微嵌合现象有助于某些自身免疫性疾病（特别是 SLE）的发病机制。 拟议的研究将调查持续母体微嵌合现象的定性和定量方面。 为了进一步解决 SLE 患者受致病性疾病影响的组织，将检查母体 DNA 和细胞。 母亲及其后代的 HLA 关系将作为持续性母体微嵌合现象的持续性和/或致病性的潜在因素进行研究。 所提出的研究可能会导致对免疫学方面和妊娠后果的新认识。 如果持续的母体微嵌合参与 SLE 的发病机制，则可以在此基础上开发新的治疗方式。